IGF-1R is a receptor tyrosine kinase which has a structure extremely similar to that of an insulin receptor and is a heterotetramer consisting of 2 extracellular α subunits and 2 transmembrane β subunits [EMBO Journal, vol. 5, p. 2503 (1986); Annual Review of Biochemistry, vol. 69, p. 373 (2000)]. By binding insulin-like growth factor-1 or 2, which is a ligand of IGF-1R, to its α subunits, the β subunits having kinase domain activate and thereby causes activation of IGF-1R. The activated IGF-1R phosphorylates many important proximal substrates such as insulin receptor substrate-1 or 2, and activates Akt, which is a serine-threonine kinase, via phosphatidylinositol-3 kinase or activates mitogen-activated protein kinase (MAPK) [Endocrinology, vol. 142, p. 1073 (2001)]. A signal pathway of Akt or MAPK is known to take an important role in transformation, proliferation, survival, infiltration and transfer of cells [Current Cancer Drug Targets, vol. 4, p. 235 (2004); and Molecular Pathology, vol. 54, p. 149 (2001)]. Also, signals sent from IGF-1R are known to protect cancer cells from cell-killing effect by chemotherapy or actinotherapy and are thought to be an important factor of drug tolerance [Breast Cancer Research and Treatment, vol. 56, p. 1 (1999); Cancer Research, vol. 57, p. 3079 (1997)]. Therefore, blocking these signal pathways is considered as an effective method for cancer treatment.
In many cancer cells (such as lung cancer, colon cancer, pancreatic cancer, mammary cancer, prostatic cancer, hepatic cancer, melanoma, brain tumor, multiple myeloma and leukemia), increase of expression of IGF-1R or activation of IGF-1R is known to be observed [Endocrine Reviews, vol. 21, p. 215 (2000); Nature Reviews Cancer, vol. 4, p. 505 (2004)]. Also, in rare cases, amplification of chromosomes, in which IGF-1R exist, are also known in mammary cancer or melanoma [Genes Chromosomes Cancer, vol. 11, p. 63 (1994)].
Therefore, IGF-1R is thought to be an effective target for cancer treatment and IGF-1R inhibitor is thought to be an useful therapeutic agent for various cancers.
Heretofore, staurosporine has been widely known as a kinase inhibitor [Biochemical & Biophysical Research Communications, vol. 135, p. 397 (1986)]. However, staurosporine non-selectively inhibits too much kinase and therefore, when administered, it leads animals such as mice to death. On the other hand, it has been reported that imatinib developed as a selective kinase inhibitor exhibits low toxicity and high clinical effect to chronic leukemia patients by selectively inhibiting Abl (Ableson) kinase [New England Journal of Medicine, vol. 345, p. 645 (2002)].
As an IGF-1R inhibitor, a pyrimidine derivative (WO03/018021, WO03/018022, WO04/080980), a pyrrolopyrimidine derivative (WO04/043962, WO02/92599), a cyclic urea derivative (WO04/070050), a 1-phenyltetrahydronaphtalene derivative (WO04/065996) and the like are known. Also, as an indazole derivative, various compounds have been known.
In Patent Document 1, a compound represented by Formula (IA):
{wherein R1A represents a hydrogen atom, nitro, NR1A1R1A2 [wherein R1A1 and R1A2 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, lower alkanoyl (the carbon number in the lower alkanoyl is 1 to 6) or the like] or the like, R2A represents a hydrogen atom or the like, ArA represents pyridyl, substituted or unsubstituted 2-oxochromenyl [the 2-oxochromenyl is bonded to ethenyl (—CH═CH—) on its benzene ring and the substituent(s) on the 2-oxochromenyl is lower alkyl having 1 to 6 carbon atom(s) or lower alkoxy having 1 to 6 carbon atom(s)], phenyl or substituted phenyl [substituents Q1A, Q2A and Q3A on the substituted phenyl may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, nitroso, carboxy, lower alkyl having 1 to 6 carbon atom(s), lower alkoxy having 1 to 6 carbon atom(s), lower alkoxycarbonyl having 1 to 6 carbon atom(s), NR3A1R3A2 (wherein R3A1 and R3A2 have the same meanings as R1A1 and R1A2 defined above, respectively), or O(CH2)nANR3A3R3A4 (wherein nA represents an integer of 1 to 6 and R3A3 and R3A4 have the same meanings as R1A1 and R1A2 defined above, respectively), or any two from the groups Q1A, Q2A and Q3A are combined together to form —O(CR3A5R3A6)O— (wherein two terminal oxygen atoms are bonded to the phenyl group at adjacent carbon atoms on the phenyl group and R3A5 and R3A6 may be the same or different and each represents a hydrogen atom or lower alkyl having 1 to 6 carbon atom(s), or R3A5 and R3A6 are combined together to form alkylene having 4 or 5 carbon atoms), provided that the Q1A, Q2A and Q3A which are the substituents on the substituted phenyl are not simultaneously hydrogen atoms]} is disclosed.
In Patent Document 2, a compound having suppressive activity on cell differentiation represented by Formula (IB):
[wherein R4B represents CH═CH—R4B1 (wherein R4B1 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or the like) and R1B represents alkyl, aryl, CH═CH—R1B1 (wherein R1B1 represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or the like)] is disclosed.
In Patent Documents 3 and 4, a compound having inhibitory activity against c-jun N-terminal Kinase (JNK) represented by Formula (IC):
[wherein R4C represents CH═CH—R4C1 (wherein R4C1 represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or the like) and R1C represents halogen, hydroxy, amino, or the like] is disclosed. Also, a therapeutic agent for diseases associated with asbestos comprising, as an active ingredient, a compound of Patent Document 3 or 4 is known (WO2005/046594).
In Patent Document 5, a compound having inhibitory activity against JNK represented by Formula (ID):
[wherein R1D represents a hydrogen atom, NR1D1R1D2 (wherein R1D1 and R1D2 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkanoyl, or the like), or the like and R5D represents substituted or unsubstituted aryl or the like] is disclosed.
Also, in Patent Document 6, an indazole derivative having inhibitory activity against JNK is disclosed.
In Non-patent Document 1, a compound represented by Formula (IE):
(wherein R6E represents methoxy or nitro) is disclosed.
In Patent Document 7, a compound represented by Formula (IF):
[wherein WF represents a bond, or the like, XF represents a single bond, C═O, or the like, YF represents a single bond, C═O, or the like, R7F represents a hydrogen atom, alkyl optionally having substituent(s), or the like, R8F represents a hydrogen atom, or the like, R1F1, R1F2 and R1F3, which may be the same or different and each represents a hydrogen atom, halogen, or the like and R11F1 and R11F2 may be the same or different and each represents a hydrogen atom, alkyl optionally having substituent(s), or the like] is disclosed.
In Patent Document 8, a compound useful as an antitumor agent represented by Formula (IG):
[wherein R6G1 represents CONR10G1R10G2 (wherein R10G1 and R10G2 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like), or the like, R6G2 represents a hydrogen atom, substituted or unsubstituted lower alkyl or the like] is disclosed.
In Patent Document 9, a compound having inhibitory activity against protein kinase represented by Formula (IH):
[wherein R6H1, R6H2 and R6H3 may be the same or different and each represents OR11H(wherein R11H represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like), or the like] ia disclosed.
In Patent Document 10, Fms like tyrosine kinase 3 (Flt-3) inhibitor comprising, as an active ingredient, a compound represented by Formula (IJ):
[wherein XJ represents (CH2)nJ1CH═CH(CH2)nJ2 (wherein nJ1 and nJ2 may be the same or different and each represents an integer of 0 to 4), or the like, R7J represents substituted or unsubstituted aryl, or the like, R1J1, R1J2, R1J3 and R1J4 may be the same or different and each represents NR12J1R12J2 (wherein R12J1 and R12J2 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like), or the like] is disclosed.    [Patent Document 1] Japanese published Unexamined Patent Application No. 32059/1990    [Patent Document 2] WO01/53268    [Patent Document 3] WO02/10137    [Patent Document 4] WO2004/094388    [Patent Document 5] WO2004/050088    [Patent Document 6] WO03/101968    [Patent Document 7] US2005/0137171    [Patent Document 8] WO2005/012257    [Patent Document 9] WO2005/012258    [Patent Document 10] WO2005/094823    [Non-patent Document 1] Khimiya Geterotsiklicheskikh Soedinenii, vol. 7, p. 957-959, 1978